The present invention relates to novel therapeutic methods and pharmaceutical compositions for treating skin conditions and, more particularly, to compositions comprising and methods utilizing tellurium-containing compounds for treatment of basal cell carcinoma and/or actinic keratosis.
Basal cell carcinoma (BCC) is the most common form of skin cancer, affecting 800,000 Americans each year, and is, in fact, the most common malignancy in humans. Such carcinomas occur most frequently on the face, ears, neck, scalp, shoulders, and back. BCC is usually slow growing and rarely metastasizes, but it can cause significant local destruction and disfigurement if neglected or treated inadequately.
Contributing factors to BCC include exposure to radiation, such as X-ray exposure; arsenic exposure; immunosuppression; the autosomal-recessive disease, Xeroderma pigmentosum; nevoid BCC syndrome (basal cell nevus syndrome, Gorlin syndrome); Bazex syndrome; and complications of burns, scars, vaccinations, or even tattoos are contributing factors.
BCC is believed to arise from pluripotential cells within the basal layer of the epidermis or follicular structures. These cells form continuously during life and are capable of forming hair, sebaceous glands, and apocrine glands. Tumors usually arise from the epidermis and occasionally arise from the outer root sheath of a hair follicle, specifically from hair follicle stem cells residing just below the sebaceous gland duct.
The mechanism by which BCC develops is believed to include a decrease in Langerhans cells, dendritic epidermal T cells, and Thy1+ cells. Furthermore, systemic proliferation of suppressor T cells and the release of immunosuppressive factors (eg, tumor necrosis factor-a (TNF-α), interleukin-1-β (IL-1), prostaglandin (PG), interleukin 10 (IL-10) are believed to be pathogenic to the development of BCC.
In a large proportion of BCC biopsy specimens, high IL-10 expression has been found. Immunohistochemical evaluation has revealed that IL-10 is specifically localized in BCC tumor-bearing lesions, but not in the normal epidermis or dermis [1, 2]. IL-10 is not expressed in the tumor-infiltrating-lymphocytes (TIL) which attempt to destroy the tumor. Moreover, it has been demonstrated that this TIL population is inactivated by BCC-derived IL-10, resulting in their inability to respond to the tumor. Inactivation of IL-10 by anti-IL-10 neutralizing antibodies restores, in vitro, the anti-BCC TIL recognition. These findings indicate that BCC-derived IL-10 is, at least in part, responsible for immunosuppression of the local immune response. In addition, it has been found that IL-10 serves as a tumor growth factor, which constitutively activates transcription factors needed for cellular proliferation.
Treatment of BCC generally involves use of antineoplastic agents, such as 5-fluorouracil, which interferes with DNA synthesis by blocking methylation of deoxyuridylic acid and inhibiting thymidylate synthetase and, subsequently, cell proliferation; imiquimod, which is believed to increase tumor infiltration of lymphocytes, dendritic cells, and macrophages; interferon α 2-β, which is believed to act via direct antiproliferative effects against malignant cells and modulation of host immune response.
Actinic keratosis is the most common skin growth. Actinic keratoses are chiefly found on the face, the ears, the forearms, and the dorsum of the hands. However, they may occur on other areas such as the back, the chest, and the legs. They usually appear as multiple discrete, flat or elevated, verrucous, keratotic lesions. Lesions typically have an erythematosus base covered by scale (hyperkeratosis). They are usually 3-10 mm in diameter and gradually enlarge into broader, more elevated lesions. Actinic keratoses are pre-cancerous growths, which may develop into squamous cell carcinomas if left untreated.
Actinic keratosis is believed to be associated with decreased expression or activity of cytokine signal regulators. Langerhans cells, situated in the epidermis layer of the skin, have been found to have changed shape and altered function in actinic keratosis. These cells are involved in presenting presentation of antigens to T-cells. Damage to these cells results in an immunosuppressive effect on the skin. Increased incidence of actinic keratosis is found in patients having a weak or suppressed immune system.
Actinic keratosis is most commonly treated with 5-fluorouracil. Other medications include diclofenac sodium and imiquimod.
However, 5-fluorouracil may result in local erythema and hypersensitivity Further common side effects of fluorouracil include extreme fatigue; nausea; mouth sores and ulcer; diarrhea; and temporary drop in bone marrow function, causing a drop in white blood cell count, which increases the risk of severe infection, anemia and drop in blood platelets. Occasional side effects include hair thinning; brittle, chipped and ridged nails; sensitivity of the skin to sunlight; rashes; watery eyes; and loss of appetite.
Imiquimod is not indicated for treatment of tumors of the head or neck, and is not suitable for treatment of tumors of more than 2 cm in diameter. Side-effects of imiquimod include skin infection and skin rash, back pain, burning or itching, changes in skin color, diarrhea, headache, muscle aches, redness of the skin, scabbing and crusting, skin peeling, skin that becomes hard or thickened and swelling of the skin.
Common side-effects of interferon α 2-β include flu-like syndrome with fever, chills, tiredness, headache, muscle and bone aches; decreased appetite, mild nausea, mild diarrhea, seizures, irritability, poor mental concentration, and sleepiness. Less common side effects include changes in taste and dry mouth, dizziness, and abnormal results on kidney function blood tests. Rare side effects include decreased white cell count with increased risk of infection, decreased platelet count with increased risk of bleeding, vomiting, confusion, depression, chest pain, change in blood pressure, partial hair loss, rash, dry throat, irritation at the site of injection, congestive heart failure, impotence and menstrual irregularities. Incidence of severe or fatal gastrointestinal hemorrhage has been reported.
There is thus a widely recognized need for and it would be highly advantageous to have novel treatments for BCC and actinic keratosis, devoid of the above limitations.
Various tellurium compounds have been described in the art as having immunomodulating properties. A particularly effective family of tellurium-containing compounds is taught, for example, in U.S. Pat. Nos. 4,752,614; 4,761,490; 4,764,461 and 4,929,739, whereby another effective family is taught, for example, in a recently filed U.S. Provisional Patent Application No. 60/610,660, which are all incorporated by reference as if fully set forth herein. The immunomodulating properties of this family of tellurium-containing compounds is described, for example, in U.S. Pat. Nos. 4,962,207, 5,093,135, 5,102,908 and 5,213,899, which are all incorporated by reference as if fully set forth herein.
One of the most promising compounds described in these patents is ammonium trichloro(dioxyethylene-O,O′)tellurate, which is also referred to herein and in the art as AS101. AS101, as a representative example of the family of tellurium-containing compound discussed hereinabove, exhibits antiviral (Nat. Immun. Cell Growth Regul. 7(3):163-8, 1988; AIDS Res Hum Retroviruses. 8(5):613-23, 1992), and tumoricidal activity (Nature 330(6144):173-6, 1987; J. Clin. Oncol. 13(9):2342-53, 1995; J Immunol. 161(7):3536-42, 1998.
It has been suggested that AS101, as well as other tellurium-containing immunomodulators, stimulate the innate and acquired arm of the immune response. For example, it has been shown that AS101 is a potent activator of interferon (IFN) (IFN) in mice (J. Natl. Cancer Inst. 88(18):1276-84, 1996) and humans (Nat. Immun. Cell Growth Regul. 9(3):182-90, 1990; Immunology 70(4):473-7, 1990; J. Natl. Cancer Inst. 88(18):1276-84, 1996.)
It has also been demonstrated that AS101, as well as other tellurium-containing immunomodulators, induce the secretion of a spectrum of cytokines, such as IL-1α, IL-6 and TNF-α, and that macrophages are one main target for AS101 (Exp. Hematol. 23(13):1358-66, 1995) and it was found to inhibit IL-10 at the m-RNA level, and this inhibition may cause an increase in IL-12 (Cell Immunol. 176(2):180-5, 1997); J. Natl. Cancer Inst. 88(18)3276-84, 1996).
Other publications describing the immunomodulation properties of AS101 include, for example, “The immunomodulator AS101 restores T(H1) type of response suppressed by Babesia rodhaini in BALB/c mice”. Cell Immunol 1998 February; “Predominance of TH1 response in tumor-bearing mice and cancer patients treated with AS101”. J Natl Cancer Inst 1996 September; “AS-101: a modulator of in vitro T-cell proliferation”. Anticancer Drugs 1993 June; “The immunomodulator AS101 administered orally as a chemoprotective and radioprotective agent”. Int J Immunopharmacol 1992 May; “Inhibition of the reverse transcriptase activity and replication of human immunodeficiency virus type 1 by AS101 in vitro”. AIDS Res Hum Retroviruses 1992 May; “Immunomodulatory effects of AS101 on interleukin-2 production and T-lymphocyte function of lymphocytes treated with psoralens and ultraviolet A”. Photodermatol Photoimmunol Photomed 1992 February; “Use and mechanism of action of AS101 in protecting bone marrow colony forming units-granulocyte-macrophage following purging with ASTA-Z 7557”. Cancer Res 1991 Oct. 15; “The effect of the immunomodulator agent AS101 on interleukin-2 production in systemic lupus erythematosus (SLE) induced in mice by a pathogenic anti-DNA antibody”. Clin Exp Immunol 1990 March; “Toxicity study in rats of a tellurium based immunomodulating drug, AS-101: a potential drug for AIDS and cancer patients”. Arch Toxicol 1989; “The biological activity and immunotherapeutic properties of AS-101, a synthetic organotellurium compound”. Nat Immun Cell Growth Regul 1988; and “A new immunomodulating compound (AS-101) with potential therapeutic application”. Nature 1987 November.
In addition to its immunomodulatory effect, AS101 is also characterized by low toxicity. Toxicity tests have shown that LD50 values in rats following intravenous and intramuscular administration of AS101 are 500-1000 folds higher than the immunologically effective dose.
While the immunomodulating effect of tellurium-containing compounds was studied with respect to various aspects thereof, the use of tellurium compounds in the treatment of skin diseases such as basal cell carcinoma and/or actinic keratosis has never been suggested nor practiced hitherto.